Abstract: The present invention features bifunctional, soluble ecto-enzymes that are engineered to hydrolyze extracellular nucleotide triphosphates (e.g., ATP) to a nucleoside (e.g., adenosine), through the fusion of the ectodomains (ECD) of an ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) and a nucleotide monophosphatase (NMPAse), such as an ecto-5? nucleotidase (eN), alkaline phosphatase (ALP), or an acid phosphatase (AP). Also described are methods of use thereof, e.g. for limiting and decreasing inflammation and sequelae.